Pathogenic Upregulation of Glial Lipocalin-2 in the Parkinsonian Dopaminergic System

Abstract

Lipocalin-2 (LCN2) is a member of the highly heterogeneous secretory protein family of lipocalins and increases in its levels can contribute to neurodegeneration in the adult brain. However, there are no reports on the role of LCN2 in Parkinson's disease (PD). Here, we report for the first time that LCN2 expression is increased in the substantia nigra (SN) of patients with PD. In mouse brains, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment for a neurotoxin model of PD significantly upregulated LCN2 expression, mainly in reactive astrocytes in both the SN and striatum. The increased LCN2 levels contributed to neurotoxicity and neuroinflammation, resulting in disruption of the nigrostriatal dopaminergic (DA) projection and abnormal locomotor behaviors, which were ameliorated in LCN2-deficient mice. Similar to the effects of MPTP treatment, LCN2-induced neurotoxicity was also observed in the 6-hydroxydopamine (6-OHDA)-treated animal model of PD. Moreover, treatment with the iron donor ferric citrate (FC) and the iron chelator deferoxamine mesylate (DFO) increased and decreased, respectively, the LCN2-induced neurotoxicity in vivo. In addition to the in vivo results, 1-methyl-4-phenylpyridinium (MPP ϩ )-induced neurotoxicity in cocultures of mesencephalic neurons and astrocytes was reduced by LCN2 gene deficiency in the astrocytes and conditioned media derived from MPP ϩ -treated SH-SY5Y neuronal enhanced glial expression of LCN2 in vitro. Therefore, our results demonstrate that astrocytic LCN2 upregulation in the lesioned DA system may play a role as a potential pathogenic factor in PD and suggest that inhibition of LCN2 expression or activity may be useful in protecting the nigrostriatal DA system in the adult brain.

Sensitization of spinal itch transmission neurons in a mouse model of chronic itch requires an astrocytic factor

“…Furthermore, a recent study has reported that excitation of GRPR 1 neurons by GRP involves an inhibition of Kv4 channels, members of the family of voltage-gated K 1 channels, 32 but we found that LCN2 had no effect on A-type K 1 current (see Fig E7 in this article's Online Repository at www.jacionline.org), which is mainly mediated by Kv4 channels. 33 Because LCN2 has been also shown to be involved in patients with other neuroinflammatory diseases, including Parkinson disease, 34 amyotrophic lateral sclerosis, 35 and brain injury, 36 further studies are required to identify the LCN2 receptors that modulate neuronal activity.…”

Early Gene Expression Profile in Retinal Ganglion Cell Layer After Optic Nerve Crush in Mice

“…87,93 Although Lcn2 functions in nervous systems are not fully understood yet, in addition to optic neuropathy, 34,35,41,44,[47][48][49][94][95][96] Lcn2 expression is also known to be induced in neurologic diseases, such as multiple sclerosis, 97,98 Alzheimer's disease, 99 and Parkinson's disease. 100 In these neurologic diseases, the disruption of iron homeostasis is a hallmark feature of affected regions. 101 Lcn2 mediates cellular iron revel through its receptor 24p3R, and this process induces upregulation of proapoptotic molecule Bim, a member of the Bcl-2 family.…”

Dynamic Changes in the Nigrostriatal Pathway in the MPTP Mouse Model of Parkinson’s Disease

“…The effects of exaggerated inflammatory responses on microglia are mainly considered deleterious [ 28 ]. Inhibition or attenuation of microglial activation is related to dopaminergic neuroprotection [ 29 – 32 ], with the exception of the report on IL-6 knockout mice [ 33 ]. However, the effects of reactive astrocytes are still controversial.…”